Genetic instability, an important hallmark of cancer, can occur at two different levels. First, increased mutation rates can result from defective repair of damaged DNA or replication errors. Second, improper segregation of whole chromosomes or pieces of chromosomes during mitosis can lead to aneuploidy or translocations, traits commonly observed in cancer. Associations of oncoproteins or tumor suppressor proteins with the process of chromosome segregation provide links between chromosomal instability and carcinogenesis.
Hec1, a coiled-coil protein that is highly expressed in most cancer cells, appears to be crucial for faithful chromosome segregation. Cells microinjected with anti-Hec1 antibodies undergo aberrant mitosis, with grossly unequal distribution of chromosomes. Furthermore, Hec1 associates with several proteins required for G2/M phase progression, including components of the 26S proteasome, Smc1/2, and the NimA-like protein kinase Nek2. Nek2 has significant sequence homology with NimA, a serine/threonine kinase required for passage of fungi past G2 into M phase, exit from M phase, and response to DNA damage. A yeast homolog of HEC1 (scHec1) is essential for yeast survival and plays an important role in chromosome segregation. Human HEC1 (hsHec1) can fulfill all essential functions in S. cerevesiae null for scHec1, suggesting that fundamental mechanisms governing chromosome segregation are highly conserved in evolutionarily divergent species.
In view of the high incidence of cancers and the lack of efficacious treatments for many types of cancer, there is a need in the art for new therapeutic targets and new approaches for cancer treatment.